Citation Manager Formats

Share

Abstract

The approval of tissue plasminogen activator (tPA) for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of an acute stroke. Despite this approval and the lack of an alternative therapy, the use of tPA in stroke has been quite low. Several explanations for this underutilization have been identified, including lack of patient awareness, potential complications, infrastructure deficiencies, and physician concerns. This article explores these issues and suggests strategies for improving the use of tPA as an acute therapy in stroke.

More than a year has passed since the United States Food and Drug Administration (FDA) approved tissue plasminogen activator (tPA) as the first(and thus far the only) therapy for reversing or reducing the effects of acute ischemic stroke. Despite this important advance, the use of tPA in patients with stroke has been limited. According to market research, approximately 6,000 patients with stroke in the United States were treated with IV tPA in the 12 months since its approval. However, an estimated 400,000 patients annually are diagnosed with acute ischemic stroke, so it appears that only 1.5% of patients who might be candidates for tPA therapy are actually receiving it. Even when the many contraindications to tPA are considered, this therapy still appears to be significantly underutilized in patients with ischemic stroke. This situation is considerably worse than that encountered with the introduction of tPA for myocardial infarction.1,2

Four main reasons have emerged for this underutilization of tPA in stroke:(a) few of the patients with ischemic stroke present for medical care within the 3-hour time window required for tPA; (b) physicians are concerned about the efficacy of tPA; (c) physicians fear the complications of tPA, particularly bleeding; and (d) the infrastructure for appropriate administration of tPA within the 3-hour time window is inadequate.

Public awareness. The paucity of public knowledge about the signs and symptoms of stroke often results in a delay in seeking medical care and is perhaps the most significant factor limiting the use of tPA in stroke.3-5 For example, the International Stroke Trial (IST), which included over 19,000 patients randomized to receive aspirin, heparin, both, or neither within 48 hours of symptom onset, found that only 4% of patients presented within 3 hours of symptom onset and only 16% presented within 6 hours of onset (table 1).6

To increase public awareness, several national and regional groups, including the American Heart Association, National Stroke Association, American Academy of Neurology, and Stroke Belt Consortium, have begun sponsoring local, regional, and national public education forums on stroke.7,8 These efforts should lead to an increase in the number of patients with stroke who seek medical care within the first few hours of symptom onset and thus to an increase in the use of tPA. More widespread public education also may promote research and testing of other acute stoke therapies, such as neuroprotective agents.

Physician concern: efficacy. Despite FDA approval of tPA for acute ischemic stroke, a large percentage of physicians have not embraced its use. The American College of Emergency Physicians has recommended "with reservations" the use of tPA for acute stroke.9 Among the explanations for this provisional support is physician reluctance to use an agent backed by the results of only one positive clinical trial [the NINDS(National Institute of Neurological Disorders and Stroke) rt-PA Stroke Study10], particularly when a number of other published study conclusions have been negative or equivocal.11-13 However, the NINDS study was actually a two-part study, with both part A and part B demonstrating the efficacy of tPA.14 Efficacy was observed in patients treated within 90 minutes of stroke onset and in those treated between 91 and 180 minutes of stroke onset. The magnitude of efficacy was impressive, with an 11 to 13% absolute increase in the number of tPA-treated patients exhibiting minimal or no neurologic deficits or disabilities compared with placebo-treated patients. The relative efficacy was even greater. The study reported a 30 to 55% relative improvement in clinical outcome for tPA-treated patients compared with placebo-treated patients.10 Efficacy was observed for all types of stroke, including atherothrombotic large vessel disease, cardioembolic stroke, and lacunar (small vessel) stroke.

In comparison, the other thrombolytic studies were less stringent in their eligibility criteria and in their enforcement of these criteria. In addition, these studies evaluated higher doses of tPA, other thrombolytic agents (e.g., streptokinase, urokinase), longer time windows for treatment (4 or 6 hours), and the use of concomitant medications, such as aspirin and heparin, that may increase the risk of bleeding.10-13

The issue of efficacy also has been studied in a large meta-analysis that evaluated the combined benefits of various thrombolytic agents for acute ischemic stroke.15 Although this analysis found an excessive number of cases of symptomatic intracerebral hemorrhage (ICH) in all treatment groups, it also found that thrombolytic therapy reduced the overall occurrence of death and dependence. In addition, a subanalysis of patients treated within 3 hours of symptom onset yielded favorable outcomes for the end points of death and dependence at the end of follow-up.15 Although fraught with problems because of the significant heterogeneity in study designs, differences in drugs studied, and concomitant medications, as well as varying inclusion and exclusion criteria, the meta-analysis tends to support the validity of the findings in the NINDS study.

Physician concern: safety. Another key concern physicians have expressed with tPA is the risk of serious bleeding complications.16 In the NINDS study, the occurrence of symptomatic ICH was 6.4% in the tPA-treated group compared with 0.64% in the placebo-treated group. Fatal ICH occurred in 2.9% of tPA-treated patients and 0.3% of placebo-treated patients.10 Subsequent studies have identified two clinical predictors of serious ICH: ischemia as observed on the baseline CT scan of the head and a stroke severity score of >20 on the NIH Stroke Scale. Early changes on CT scans were the most significant factor, yielding an odds ratio of 7.8 in predicting symptomatic ICH.17 Even in this high-risk population, an overall benefit from tPA therapy was observed.

In considering the use of tPA for stroke, one might find a comparison with other high-risk neurologic interventions helpful. For example, patients diagnosed with a transient ischemic attack caused by high-grade carotid artery stenosis frequently are referred for carotid endarterectomy. The risk of stroke or death with this procedure in this patient population is 5 to 8%, which is similar to, if not greater than, the risk of serious ICH or death with tPA treatment in patients with stroke.18-20 Patients also should be made aware of the risk. At our medical center, we try to prevent misunderstandings about the risks of therapy by routinely asking patients or their next of kin to sign a consent form that specifically describes a 6% risk of brain hemorrhage and a 3% risk of fatal brain hemorrhage with tPA therapy for acute ischemic stroke.

Infrastructure issues. To use tPA safely and effectively, treatment facilities must have the proper infrastructure(table 2). A key component is advanced training for the treating physician. Although neurologists may have the expertise to administer tPA, the vast majority of patients with stroke in the United States are treated in the acute stages of their illness by non-neurologists. In fact, neurologists are the attending physicians for only 11% of acute stroke patients.21 Therefore, all physicians who might treat patients with stroke (especially emergency physicians and members of an acute treatment team) must be familiar not only with procedures for diagnosing and treating acute stroke but also with the proper use of thrombolytic agents.22

Many medical centers and hospitals are establishing acute stroke teams so that they can provide rapid, accurate acute stroke care.23,24 These teams are composed of a small group of physicians(including non-neurologists), nurses, and others trained to treat patients with acute stroke. Formation of such teams ensures that the center has an expert group of professionals able to diagnose stroke and administer acute stroke therapies. Facilities that lack physicians with experience in cerebrovascular disease may be able to take advantage of telemedicine technology to gain prompt neurologic expertise.

Another important requirement is the availability of CT scanning facilities on a 24-hour-per-day, 7-day-per-week basis. The time between patient presentation and performance of a CT head scan must be kept to a minimum. An experienced radiologist must be available to interpret the CT scan and detect early signs of ischemic stroke and to help identify patients at increased risk for ICH after tPA therapy.17,22

All treatment centers should develop a written tPA protocol incorporating the recommendations of the FDA and perhaps additional guidelines from peer-reviewed medical journals.22 In addition, treatment centers are encouraged to establish a stroke unit or an intensive care unit in which patients with stroke who are given tPA can be monitored closely for complications for at least the first 24 hours after therapy.

Conclusions. Several ongoing phase III clinical trials, including the European Cooperative Acute Stroke Study II (ECASS II) and ATLANTIS, are continuing to evaluate the safety and efficacy of tPA in patients with acute stroke. Neuroprotective agents also are being evaluated for use in acute stroke.25 At present, however, IV tPA administered within 3 hours of stroke onset is the only approved therapy for acute ischemic stroke in the United States.22 Physicians who choose to use this therapy should be familiar with the treatment guidelines for administering tPA to stroke patients because they differ considerably from those used for tPA in treating acute myocardial infarction.14,22 Expanding the use of this agent could have significant benefits for many patients who present with acute ischemic stroke.

Marler JR, Jones RW, Emr M. Proceedings of a national symposium on rapid identification and treatment of acute stroke. Bethesda, MD: The National Institute of Neurological Disorders and Stroke, National Institutes of Health, 1997.

Disputes & Debates: Rapid online correspondence

NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

Stay timely. Submit only on articles published within the last 8 weeks.

Do not be redundant. Read any comments already posted on the article prior to submission.

200 words maximum.

5 references maximum. Reference 1 must be the article on which you are commenting.

5 authors maximum. Exception: replies can include all original authors of the article.

Submitted comments are subject to editing and editor review prior to posting.

I, the first and corresponding author, verify that I have read the contents of the PUBLISHING AGREEMENT form. *

I, the first and corresponding author, verify my disclosures and those of my co-authors are up to date at http://submit.neurology.org. *

Select only one of the three options below: *

I am an Author of this Work, and the Work was prepared on my own time - not as part of my duties as an employee.

I prepared (or cooperated in the preparation of) the Work as part of my duties as an employee, and the Work is, therefore, a "work made for hire", as defined by the United States Copyright Act of 1976, as amended.

I prepared (or participated in the preparation of) the Work as part of my official duties as an officer or employee of the United States Government.

NOTE: All authors, besides the first/corresponding author, must complete a separate Disputes & Debates Submission Form and provide via email to the editorial office before comments can be posted.

CAPTCHA

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.